(R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)-cyclopropyl) benzoic acid or its salt also in polymorphic form a for use in the prevention of heterotopic ossification

Abstract

There is described a compound of formula (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)-cyclopropyl)benzoic acid or a pharmaceutically acceptable salt thereof or the form A of its sodium salt for use in the prevention of heterotopic ossification. Preferably such a compound is effective in a specific dose range.

The invention claimed is: 
     
       1. A method for the prevention of heterotopic ossification in a subject affected by a disease selected from the group consisting of Myositis Ossificans, Post Surgical Heterotopic Ossification, Post-Injury Ossification, Osteosarcoma, at least one Spondyloarthropathy, at least one Seronegative arthropathy, Diffuse idiopathic skeletal hyperostosis, Para-articular Ossification, at least one Crystal-Induced Arthropathy, Osteoarthritis driven by degenerative processes, Hyperparathyroidism, Drug-Induced Ossification, and Ochronosis, Diffuse Idiopathic Skeletal Hyperstosis, Fibrodysplasia ossificans progressive, Synovial Endochromatosis and Progressive Osseous Heteroplasia, wherein said method comprises the step of administering to the subject a compound of formula (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)-cyclopropyl)benzoic acid or a pharmaceutically acceptable salt thereof. 
     
     
       2. The method of  claim 1 , wherein the pharmaceutically acceptable salt is the sodium salt. 
     
     
       3. The method of  claim 2 , wherein the sodium salt of (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)-cyclopropyl)benzoic acid is a polymorphic form of sodium salt of (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoic acid characterized by a powder XRD spectrum with peaks at values of the angle 2θ±0.2° of 4.3, 5.0, 5.8, 6.4, 7.1, 8.3, 8.7, 12.8, 15.3, 15.9 (form A), said powder XRD spectrum recorded using a Cu K(α) radiation source, with wavelength values λ 1 =1.54051 Å and λ 2 =1.54430 Å. 
     
     
       4. The method according to  claim 1 , wherein the compound of formula (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoic acid or its salt or the form A of its sodium salt is in a dose in the range from 1 to 30 mg/kg. 
     
     
       5. The method according  claim 4 , wherein the compound of formula (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)-cyclopropyl)benzoic acid or its salt or the form A of its sodium salt is in a dose in the range from 8 to 20 mg/kg. 
     
     
       6. The method according  claim 5 , wherein the compound of formula (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)-cyclopropyl)benzoic acid or its salt or the form A of its sodium salt is in a dose of about 10 mg/kg. 
     
     
       7. The method according to  claim 1 , wherein the at least one Spondyloarthropathy is selected from the group consisting of Ankylosing spondylitis and Psoriatic arthritis. 
     
     
       8. The method according to  claim 1 , wherein the Diffuse Idiopathic Skeletal Hyperstosis is caused by metabolic and/or degenerative processes. 
     
     
       9. A method for the prevention of heterotopic ossification in a subject affected by a disease selected from the group consisting of Myositis Ossificans, Post Surgical Heterotopic Ossification, Post-Injury Ossification, Osteosarcoma, at least one Spondyloarthropathy, at least one Seronegative arthropathy, Diffuse idiopathic skeletal hyperostosis, Para-articular Ossification, at least one Crystal-Induced Arthropathy, Osteoarthritis driven by degenerative processes, Hyperparathyroidism, Drug-Induced Ossification, and Ochronosis, Diffuse Idiopathic Skeletal Hyperstosis, Fibrodysplasia ossificans progressive, Synovial Endochromatosis and Progressive Osseous Heteroplasia, wherein said method comprises the step of administering to the subject a pharmaceutical composition comprising the compound of formula (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)-benzoic acid or a pharmaceutically acceptable salt or the form A of its sodium salt and at least one pharmaceutically acceptable excipient. 
     
     
       10. The method according to  claim 9 , wherein the compound of formula (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoic acid or its salt or the form A of its sodium salt is in a dose in the range from 1 to 30 mg/kg. 
     
     
       11. The method according  claim 10 , wherein the compound of formula (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)-cyclopropyl)benzoic acid or its salt or the form A of its sodium salt is in a dose in the range from 8 to 20 mg/kg. 
     
     
       12. The method according  claim 11 , wherein the compound of formula (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)-cyclopropyl)benzoic acid or its salt or the form A of its sodium salt is in a dose of about 10 mg/kg. 
     
     
       13. The method according to  claim 9 , wherein the at least one Spondyloarthropathy is selected from the group consisting of Ankylosing spondylitis and Psoriatic arthritis. 
     
     
       14. The method according to  claim 9 , wherein the Diffuse Idiopathic Skeletal Hyperstosis is caused by metabolic and/or degenerative processes.